Powerful imaging methods currently exist which enable one to assess the living brain and body in vivo and thereby monitor the effectiveness of treatments that affect brain chemistry and function. Positron emission tomography (PET) is a dynamic, non-invasive imaging technique used in nuclear medicine to study various biochemical and biological process in vivo. In PET, labeled compounds may be administered in nanomolar or picomolar concentrations, allowing imaging studies to be performed without perturbing the biological system being studied. These labeled compounds may generally be radioisotopes that give off positrons. The emitted positrons may then collide with electrons, which generates gamma rays. The emitted gamma rays may then be detected by scanners and be processed to obtain images of the living brain and body. Like other dynamic imaging protocols, PET has the ability collect images repeatedly over time and provide information about regional distribution of the tracer as well as the change in compartmental distribution as a function of time. As such, PET lends itself directly to measuring kinetic processes, such as rate of tracer uptake by cells, substrate metabolic rates, receptor density/affinity, and regional blood flow.
Serotonin system in the brain is an important neurotransmission network regulating various physiological functions and behavior including anxiety and mood states. Serotonin (5-hydroxytryptamine; 5-HT) has been linked with major depression, bipolar disorder, eating disorders, alcoholism, pain, anxiety, obsessive-compulsive disorders, Alzheimer's Disease, Parkinson's disease and other psychiatric maladies. It is also involved in mediating the action of many psychotropic drugs including antidepressants, antianxiety drugs and antipsychotics. There are more than a dozen known subtypes of serotonin receptors. Among these serotonin receptors, 5-HT1A receptors play a role as a presynaptic autoreceptor in the dorsal raphe nucleus and as a postsynaptic receptor for serotonin in terminal field areas.
Several radioligands for 5-HT1A receptors have been prepared and evaluated. The most successful radioligands studied so far for 5-HT1A receptors are antagonist tracers which bind with both the G-protein-coupled high affinity (HA) state and uncoupled low affinity (LA) state of 5-HT1A receptors. In contrast, agonists bind preferentially to the HA state of the 5-HT1A receptor. Therefore, having a radioligand agonist tracer may provide a more meaningful functional measure of 5-HT1A receptors. To date there are no successful 5-HT1A agonist radiotracers available for studies in a living brain.
Thus, there is still a need in the art for radiolabeled serotonin agonist modulators that are highly selective for imaging 5-HT1A receptors. Moreover, there remains a need in the art for selective radioactive tracers, which are useful for imaging 5-HT1A receptors in vivo. The present invention addresses these needs.